Tetrahydroindazoles



United States Patent 3,520,901 TETRAHYDROINDAZOLES GiangiacomoMassaroli, Milan, Italy, assignor to Polichimica Sap S.p.A., Milan,Italy No Drawing. Filed July 7, 1967, Ser. No. 651,675 Claims priority,application Italy, July 16, 1966, 16,562/ 66; Apr. 4, 1967, 14,556/ 67Int. Cl. C07d 49/20 US. Cl. 260-310 28 Claims ABSTRACT OF THE DISCLOSURENew substituted 3 amino-tetrahydroindazole compounds possessinganti-inflammatory properties, and process for the preparation thereof;said compounds conforming to the general formula:

wherein R represents hydrogen or lower alkyl, R represents hydrogen,lower alkyl, p-hydroxyethyl,

phenyl, halophenyl, (lower alkoxy)phenyl, --COOC H OH COOC H benzoyl,halobenzoyl, or (lower alkoxy) benzoyl, and R when a benzoyl group isalternatively in the l-position of the indazole ring, R representshydrogen, lower alkyl, carboxyl or CSNHCH and R represents lower alkyl,lower alkenyl or aralkyl and their non-toxic acid addition salts.

This invention relates to 3-amino-tetra-hydroindazoles and theirproduction.

The present invention provides the new 3-amino-tet1'ahydroindazoles ofthe general formula:

R represents hydrogen or lower alkyl, R represents hydrogen, loweralkyl, fl-hydroxyethyl,

phenyl, halophenyl, (lower alkoxy)phenyl, -COOC H CH COOC H benzoyl,halobenzoyl, or (lower alkoxy) benzoyl, and R when a benzoyl group isalternatively in the l-position of the indazole ring, R representshydrogen, lower alkyl, carboxyl, or CSNHCH and R represents lower alkyl,lower alkenyl or aralkyl and their nontoxic acid addition salts. Bylower alkyl, lower alkoxy, and lower alkenyl are meant alkyl, alkoxy andalkenyl radicals of up to 4 carbon atoms each.

3,520,901 Patented July 21, 1970 According to the invention, thecompounds of general Formula I are obtained by reacting anenamino-thiocarboalkylamide of the formula:

S ill-NHR:

where A represents an N-morpholino, N-pyrrolidino, or N-piperidinoresidue and R and R are as hereinbefore defined, or the correspondingketone, obtained from 11 by mild hydrolysis, with a hydrazine of theformula: R NHNH where R; is as hereinbefore defined, and the so-obtainedcompound of the formula NHRg /Ra /Ra N N 41 R R E R2 R2 -It follows thatwhen a compound of Formula I in which R is hydrogen, is acylated, theacyl group may attach itself to the 1- or 2-position. When ahalo-benzoyl of (lower alkoxy)benzoyl chloride is used for thisacylation, the substituent is ordinarily in the para-position.

The compounds of Formula II may themselves be made by the reaction of acompound of the formula:

with an isothiocyanate of the formula: R NCS, where R R and A are ashereinbefore defined. This reaction may be efiected by heating equimolarproportions of the reactants for 6-8 hours on a water-bath, at atemperature in the range of 100 C. The product is generally employed inthe crude state in the subsequent reaction with the hydrazine offormula: R NLHNH Thus, the enamino-bis-thiocarbomethylamide of FormulaII where A is morpholino, R is CSNHCH and R 3 is CH may be prepared byreacting 1 mole of the corresponding enamine of Formula IV wherein R=CSNHCH with 1 mole of methyl isothiocyanate, or directly from 1-morpholinocyclohexane by reaction with 2 moles of methyl isothiocyanate.However, even better results are 4 ylation of the amino nitrogen, not ofthe heterocyclic nitrogen. This is proved by the fact that reaction ofthe compound of Formula I in which R, R and R are hydrogen and R ismethyl with formaldehyde and formic acid gives a compound which isdifferent from that ohobtained by reacting 2 moles of methylisothiocyanate tained by reaction of the compound of Formula II in with1 mole of 1-N-pyrrolidino-cyclohexane. The l-pyI- which R is hydrogen, Ris methyl, and A is morpholino rolidino-2,6di(thiocarbomethylamino)-1-cyclohexene so with CH NHNH The formercompound is able to react obtained behaves in the subsequent processsteps like the with benzoyl chloride to give a compound of Formula Icorresponding 1- morpholino-2,6-di(thiocarbomethylamiwherein R ishydrogen, R and R are methyl, and R is no) -l-cyclohexene. benzoyl.

For the preparation of compounds of general Formula The compounds ofFormula I show analgesic and anti- I (wherein R =CSNHCH R=H, R =CH andinflammatory activity, as shown in the following Table 1, R =phenyl orone of the groups listed in Table 4), the wherein the activity of thenew compounds is compared 2,6-di(thiocarbomethylamino)-l-cyclohexanone,obtained with that of two known analgesic and anti-inflammatory from IIwhere A is pyrrolidino, R is CSNHCH and R is substances, aminopyrine andphenylbutazone. In partic- CH by mild acidic hydrolysis, has beenpreferably subular it may be noted that aminopyrine shows goodanaljected to the reaction with the hydrazine of formula gesicproperties, but poor anti-inflammatory properties R NHNH in which R=phenyl or one of the groups and phenylbutazone shows goodanti-inflammatory proplisted in Table 4. erties but poor analgesicactivity. However, several com- The course of the reaction between thecompounds of pounds of the present invention show both analgesic andFormula II and the hydrazines of formula R NI-INH anti-inflammatoryactivities simultaneously to a high deand the ensuing position of thesubstituent R in the ingree, so that the new compounds are superior toaminodazole nucleus produced, follows in general the scheme py-rine andphenylbutazone in the treatment of rheumatic ascertained by Pocaret-al., Gazz. Chim. Ital., 93, l00-l13 diseases wherein ananti-inflammatory and an analgesic (1963). Hydrazone formation occurs,and the hydrazone action are simultaneously required. cyclizes withsplitting off of hydrogen sulphide. The various kinds of activityindicated in Table l were When R is ethoxycarbonyl, the course of thereaction determined by the following tests of the hydrazine of formula RNHNH with the compound of Formula II depends in part on the nature ofthe 2 i g jg and Franceschlm Pharmacol" iubstlmqnt Thusiwhen R2=CSNHCH3the Compound (b) Test of Randall and Selitto, Arch. Int. Pharmacodyn,

ormed is one in which R is ethoxycarbonyl and R rep- 4 409 (1957)resents CSNHCH3 Whereas the R ED356118. (c) Test of Hendershot andFors-aith, J. Pharmacol. Exp. or methyl, the compound formed 1s one inWhlCh the m- 237 (1959) dazole nucleus is free of substituents in land2-positions. 35 (d) Test of Winter et al, PharmacoL Ther 141,

Reaction of tetrahydroindazoles of general Formula I 3 9 19 where R andR are both hydrogen with the calculated (6) Test f Wilhelmi, SchweizWochr. 88, amount of formaldehyde and formic acid leads to meth- (1958).

TABLE 1 N R1 R3 Oom- R; N pound 1 R R1 R2 R3 2 H H a H CSNHCH: CH3

4 H COOH CH3 5 H H 6 H H H CH3 7 H o1-- CSNHOHa CH3 8 CH; -0 og 8%;

9 H CH H CH 10 H 430002115 CSNHCHa CH3 11 CH; oo c 0- H GHQ 12 CH3omoQ-o 0- H CH;

13 H omoQ- CSNHOH; CH

TABLE 1-Continued a N NRi Com- R2 pound 14..-.- H CH2COOC2H5 H OH;

H H CH: OH;

R R1 Ra Rs 16. H CH3 CSN H011 CH; 17. H CH H 02H, 18. H CH4 H i-C3H 19-.H CH3 H Il-C H9 20-... H CH3 H C5H5OH2 21.- H OH: H -CHzCH=CH2 22. H CH3H 11-O3H7 23- H CHzCHzCH H CH 24. H Il-C 4H9 H 0 H3 25. H C2115 H CH 26.H 11-C3H7 H CH3 27--. H CHzCHOHCHzSCHz H CH 28.-. Amiuopyrme 29Phenylbutazone Analgesic Activity Anti-Inflammatory Activity LD Non-Granu- Perltoi inflam- Infiamloma from Oedoma nitis mice matory matoryp-Quinone cotton from from per os Oompain pain test pellets carrageninformalin (mg./ Pound (0 Illllll Llll|lllll l Substituent R1 is probablylinked to I-position of indazole ring.

The following examples illustrate the invention.

EXAMPLE 1 1-morph0lino-2-thiocarbomethylamino-l-cyelohexene In a 500 ml.flask provided with condenser and protected against the moisture bymeans of a calcium chloride tube, 80.3 g. (1.1 moles) of methylisothiocyanate and 167 g. (1 mole) of l-morpholino-cyclohexene areintroduced. The mixture is heated for 6 hours on a water-bath at 75 85C. and then diluted with 250 ml. of diisopropyl ether and stirredvigorously while it cools. After a short time the Oily suspensionsolidifies into a yellow mass which is allowed to stand overnight,filtered off and washed with diisopropyl ether. 215 g. (90%) ofl-morpholino 2 thiocarbomethylamino-l-cyclohexene are obtained, whichafter recrystallization from the smallest amount of methanol melts at8183 C.

Analysis.-Calc. for C H N OS (percent): N=11.66, 8:13.33. Found(percent): N=11.44, 8:13.21.

Proceeding in the same manner from equi-molar amounts ofl-morpholino-6-methyl-1-cyclohexene and methylixothiocyanate, a 30%yield is obtained of l-morpholino Z-thiocarbomethylamino-6methyl-l-cyclohexene as a yellow compound melting at -149 C.

Analysis-Cale for C H N OS (percent): 8:12.59. Found (percent): 8:12.40.

EXAMPLE 2 2, 6 -di- (thiocarbomethylamino l-cyclohexanone Into awide-necked flask containing 14.6 g. (0.2 mole) of methylisothiocyanate, 15.1 g. (0.1 mole) of 1-pyrrolidino-l-cyclohexene areintroduced with stirring within about 30 minutes, while the temperatureis kept below 40 C. with an ice bath. At the end of the re- 7 action,the bath is removed, and the flask is allowed to stand at roomtemperature for 24-36 hours. 3055 ml. of diisopropyl ether are added tothe thick reaction mass, which is then triturated until it solidifies.The yellow solid product is filtered 01f, air-dried, and suspended 8Analysis-Cale. for C H N .HCl (percent):

N=22.45. Found (percent): N=22.74.

The hydrochloric acid titre is 99.1% of theory. By an identical process,equimolar amounts of l-morin ethanol (1 ml./g.). Dilute hydrochloricacid (1:1) 5 pholino-6-methyl-l-cyclohexene and ethoxycarbonyl hyisadded until the mixture has a persistent acid reaction, drazine arereacted, and 3-methylamino-7-methyl-4,5,6,7- and 5-6 volumes of waterare th n added. An oil tetrahydroindazole hydrochloride, M.P. 189191 C.,separates which solidifies within a few hours. The solid i btain dinayield of 56%. is filtered oh and recrystallized from ethanol. 12.3 g.Analysis.Calc. for C H N .HCl (percent): (50%) of 2,6-di(thiocarbomethylamino)-l-cyclohex- 39 anone, M.P. 148-150 C., areobtained. F d (percent): N=20 96,

y for m is z z (P 5:26-22, The hydrochloric acid titre is 100% oftheory. N=1l.47. Found (percent): S=25.5, N=11.77. E A L 5 EXAMPLE 3 15X MP E 2 pheny1 3 methylamino 45674etrahYdroindaZole2-methyl-3-methylam1no-4,5,6,7-tetrahydro1ndazole Into a 250 flask 133((1055 mole) of Lmoi A solution of 50.6 g. (1.1 moles) of methylhydrazine pholino-Z-thiocarbomethylamino-l-cyclohexene, 7.92 g. m abolute 1sdropped about 30 0355 mole) f phenylhydrazine hydrochloride, and 70 2Outes 1nto a stirred mixture of 240 g. (1 mole) of crude ml. of 95%ethanol are introduced. The mixture is boiled 1 morpholmo 2thlocalbomethylammo 1 cyclo under reflux for 6 hours, the solvent isevaporated in of absolute ethanPl and (2 moles) vacuo and the residue istriturated with diethyl ether of acct; The temperature 15 P thls firstStep to separate the morpholino hydrochloride, which is At the end f theaddition, when the gas filtered ff The filtrate is evaporated todryness, and evolution has slackened, the mixture is heated to boilingml. of dilute hydrochloric acid (1:1) are added to the and refluxed for3 then F P Q in a residue. The mixture is boiled for minutes with char-Vacuum and the resldue 1S Wlth lltl'es of coal and filtered hot. Aftercooling, the crystals which fi About 80 of tartarlc 361d are added andth eparate are filt d ff, h d i h acetone d dimixture is allowed tostand overnight. Activated charcoal ethyl ether until colourless, dried,and finally recrystal- 30 is added, the separated tarry products areremoved, and lized from Water. They then melt at 182-184 C. The thesolution is concentrated in vacuo to /3 of its original yield is 65%.volume and saturated with solid potassium carbonate.

Analysis--calculated for m n a (P 0 The organic layer is extracted withbenzene, and the ex- Found (Percent): tract is dried over sodiumsulphate and evaporated in It contained the theoretical proportion ofhydrochloric vacuo The 1 3 dfstlued at 0-05-01 acid torr and thedistlllate 1s recrystallized from dusopropyl By the same method thecompounds listed in the folether- It lowing Table 2 are obtained fromequimolar amounts y for C9H15N3 (P of the appropriate startingmaterials. 40 F und (percent): N= 25.l2.

TABLE 2 NH-OHg-HCI N-Ri \N/ Analysis Hydro- Cl percent N percentchloride Yield, titre, M.P., R1 percent Cale. Found Cale. Found percentC.

Cl-Q- 63.7 23.91 23.82 14.14 13.86 99.5 162-164 CH3O- 14. 33 14. 31 100.6 178-180 --OH COOC2H 15.38 15.62 100.2 145-147 EXAMPLE 4 60 Itsacidimetric titre is 100.3% of theory. The maleate3-methylamino-4,5,6,7-tetrahydroindazole melts at 150453 Into a 250 ml.flask are introduced 27 g. (0.1125 mole) EXAMPLE 6 of1-morpholino-2-thiocarbomethylamino-l-cyclohexene, 2 methy1 3ethy1a.mino 4,5,6,7 tetrahydmindazole 11.7 g. (0.1125 mole) ofethoxycarbonylhydrazine, 100 ml. of absolute ethanol, and 30 ml. ofglacial acetic 3 -5 g- (0.2 mole) of 1-morphol1no-l-cyclohexene andacid. The mixture is heated under reflux for 3 hours H1016) of methyllsothlocyanate are heated and evaporated to dryness .in a vacuum. Theresidue at 100 C. for 7 hours on a water-bath. After cooling, is takenup with diethyl ether, and the solution is 200 ml. of ligroin are addedand the mixture is stirred filtered and treated with etherealhydrochloric acid. A vigorously. The insoluble matter is allowed tosettle, is gummy precipitate is formed which is separated from separatedby decantation from the ligroin, and taken up the ether by decantationand heated with acetone to in 80 ml. ethanol and 14 ml. acetic acid, andtreated cause its solidification. The solid is filtered off and rewith 8g. (0.175 mole) of methylhydrazine. The mixture crystallized fromacetone-ethanol. 12.8 g. of 3- is refluxed for 4 hours, the solvent isremoved in vacuo, methylamino-4,5,-6,7 tetrahydroindazole hydrochloride,the residue is taken up in about 200 ml. of 10% aqueous M.P. 192194 C.,are obtained. 75 tartaric acid solution and the solution is stirred along time with charcoal and filtered. After Concentration to halfvolume, the solution is made alkaline with excess potassium carbonate,the separated oil is extracted with benzene, the benzene extract isdried over sodium sulphate and, after the solvent has been evaporated,the

10 acetone, and allowed to cool. The crystals formed are filtered off.They melt at 220-234 C.

After further recrystallization from acetone, they melt at 237-239 C.The acidimetric titre is 99.6

By an identical procedure, starting from 2-phenyl-3- residue isdistilled at 125 130 C. 0.6 torr. 5 methylamin- ,5,69 etrahydroindazole,Z-phenyl di- The distillate is disolved in a little ethanol and a con- 97' g hydrochlonde 1S centrated ethanolic solution of 17.4 g. (0.15 mole)maleic obtamed 55% yleld, 132 acid is added to it. The resultingsolution is treated with y- C1 H N .HCl (percent). N: an equal volume ofanhydrous diethyl ether and a crys- 10 PQ talline product is obtained,which when recrystallized The acldlmemc mm 15 from a littleethanol-diethyl ether, melts at 137l39 C. EXAMPLE The yield is 38%. l

Analysis.-Calc. for C H N .C H O (percent): g l g i ammo N=14.26. Found(percent): N=13.96. 15 J'tetrahY mm we The perchloric acid titre is97.9% of theory. The com- 24.4 g. (0.1 mole) of2,6-di-(thi0carbomethylamino)- pounds listed in Table 3 have beenprepared by an idenl-cyclo-hexanone, 14.4 g. (0.1 mole) ofphenylhydrazine tical process. hydrochloride, 13.8 g. (0.1 mole) ofground potassium TABLE 3 NH-Ra N-Rl N percent Acidl- Base, Yield, metricB.P. R1 R2 R3 percent M.P. Cale. Found titre C./Torr.

CH3 H (C2115) 38 137-139 1923 13. 90 97.9 125130/0.6 CH3 E 103111 34131-134" 13. 59 13.87 93.7 104 7/0.1 0H3 11 n-oim 31 97- 13.00 13. 0497.0 127-133/0.2 CH3 H CHr-CH=CH2 50 105108 13.68 13. 97.2 122-5/02 CH H011201115 42 116-118 11.76 11.72 97.7 1656/0.1 CH3 H 11-09111 117-119"13. 59 13. 02 98.2 115-120/001 02115 H CH; -11 14. 23 14.13 99.2115425/005 11-63117 H CH; 40 103-110" 13. 59 13.79 97.2 118-120/0. 01I1-G4H9 H CH; 30 109-110 13.00 12.79 98.6 -8/0. 01 CHzOHzOH H CH3 37130431 21. 53 21. 07 99.3 -3/0.2 CH2CH(OH)CH2SOH9 H CH3 25 111-113"11.32 11.41 -7/0.05

EXAMPLE 7 carbonate, and 100 ml. of 95% ethanol are refluxed with p 40stirring for 2.5 hours. The boiling solution is filtered off 3dlmethylammo tetrahydrfmdazole with suction from the salts formed andallowed to stand 11-9 g- 07 o of 3 y overnight. The crystals which haveseparated are rehydromdazole are dissolved in a water-bath in 10.5 ofcrystallized twice from absolute ethanol (2.2 ml./g.), 98% formic acid,6 ml. of 38.25% aqueous formaldehyde and Z-phenyl 3methylamino-7-thiocarbomethylami are added thereto, and the mixture isheated on a water- 5 4,5,6,7-tetrahydroindazo e, M.P. 131133 C. isobbath for 4 hours. It is then evaporated in vacuo, made tained in ayield of 80%. alkaline with potassium carbonate, and extracted withAnalysis-Cale for C H N S (percent): N=18.66; chloroform. The extract isdried over sodium sulphate, S=10,66 F und (percent); N=18 66; 5:107, andevaporated, and the white solid residue is extracted By an identicalprocedure, the compounds listed in with diethyl ether. The insolubleportion is filtered oil, 50 Table 4 are obtained from equimolar amountsof 2,6-di

the solution is dried, and ethereal hydrochloric acid is added. Theprecipitate is filtered ofiF, heated with a little(thiocarbomethylamino) 1 cyclo-hexanone and the appropriate substitutedhydrazines.

TABLE 4 NH-CH:

N-Ri SNHCHa Analysis N ercent S ercent Cl ercent Yield, M.P., p p p R1percent 0. Cale. Found Gale. Found Cale. Found COOC2Hs 70 171-173 18.9118.25 18.81 18.57

HsO-Q- 40 127-9 10.93 16.60 9.09 9.03

l Hydrochloride. 2 B ase.

1 1 EXAMPLE 9 2-phenyl-3-methylamino-7-carboxy-4,5 ,6,7-tetrahydroindazole A mixture of 3.85 g. (0.012 mole) of 2-pl1enyl-3-methylamino-7-thiocarbomethylamino 4,5,6,7 tetrahydroindazole, 4 ml. ofconcentrated sulphuric acid, 12.5 ml. of acetic acid, and 8 ml. of Wateris refluxed for 12 hours. It is then diluted with two volumes of water,the sulphuric acid is neutralized with potassium carbonate, and it isthen extracted with diethyl ether. After the ethereal solution has beenallowed to stand for some hours, a crystalline powder separates outwhich, when crystallized from aqueous ethanol, affords 2.7 g. (80%) of2-phenyl-3-methylamino-7-carboxy-4,5,6 ,7-tetrahydroindazole, M.P.156-158 C.

Analysis.Calc. for C H N O (percent): N=l5.49. Found (percent): N=15.54.

The acidimetric titre is 98.6%.

EXAMPLE 10 1 (2) -benzoyl-3-din1ethylamino-4,5,6,7- tetrahydroindazole 3g. (0.015 mole) of 3-dimethylamino-4,5,6,7-tetrahydroindazolehydrochloride are dissolved in a little water. The solution i madealkaline with potassium carbonate and extracted with diethyl ether. Theethereal solution is dried and evaporated. The residue is dissolved in20 ml. of dry benzene. To this solution 2.1 g. (0.015 mole) of finelyground potassium carbonate are added together with 2.1 g. (0.015 mole)of benzoyl chloride. The mixture is refluxed in the absence of moisturefor 6 hours and then filtered. The filtrate is evaporated in vacuo, theresidual oil is taken up with dry diethyl ether, and the solution istreated with ethereal hydrochloric acid. The precipitate is filtered offand recrystallized from acetone. It melts at 129-131 C. The yield is66%.

Analysis.--Calc. for C H N O-HCI (percent): N=13.77. Found (percent):N=14.47.

The hydrochloride titre is 100.1%.

By an identical procedure the compounds listed in Table are obtainedfrom equimolar amounts of 3-dimethylamino-4,5,6,7-tetrahydroindazole andcorresponding benzoyl chlorides.

3. 2 carbethoxymethyl 3-methylamino-4,5,6,7-tetrahydroindazole or anon-toxic acid addition salt thereof.

4. 3 methylamino 4,5,6,7-tetrahydroindazole or a non-toxic acid additionsalt thereof.

5. 3 methylamino 7-methyl-4,5,6,7-tetrahydroindazole or a non-toxic acidaddition salt thereof.

6. 2 methyl 3-methylamino-4,5,6,7-tetrahydroindazole or a non-toxic acidaddition salt thereof.

7. 2 methyl- 3-ethylamino-4,5,6,7-tetrahydroindazole or a non-toxic acidaddition salt thereof.

8. 2 methyl 3-n-propylamino-4,5,6,7-tetrahydroindazole or a non-toxicacid addition salt thereof.

9. 2 methyl 3-isopropylamino-4,5,6,7-tetrahydroindazole or a non-toxicacid addition salt thereof.

10. 2 methyl 3-n-butylamino-4,5,6,7-tetrahydr0indazole or a non-toxicacid addition salt thereof.

11. 2 methyl-3-allylamino-4,5,6,7-tetrahydroindazole or a non-toxic acidaddition salt thereof.

12. 2 methyl 3-benzylamino-4,5,6,7-tetrahydroindazole or a non-toxicacid addition salt thereof.

13. 2 ethyl 3-methylamino-4,5,6,7-tetrahydroindazole or a non-toxic acidaddition salt thereof.

14. 2 n propyl-3-methylamino-4,5,6,7-tetrahydroindazole or a non-toxicacid addition salt thereof.

15. 2 n butyl-3-methylamino-4,5,6,7-tetrahydroindazole or a non-toxicacid addition salt thereof.

16. 2 (t3 hydroxyethyl)-3-methylamino-4,5,6,7-tetrahydroindazole or anon-toxic acid addition salt thereof.

17. 2 (Bhydroxy-v-methylmercaptopropyl)-3-methylamino-4,5,6,7-tetrahydroindazoleor a non-toxic acid addition salt thereof.

18. 3 dimethylamino-4,5,6,7-tetrahydroindazole or a non-toxic acidaddition salt thereof.

19. 2 phenyl 3 dimethylamino-4,5,6,7-tetrahydroindazole or a non-toxicacid addition salt thereof.

20. 2 phenyl3-methylamino-7-thiocarbomethylamino-4,5,6,7-tetrahydroindazole or anon-toxic acid addition salt thereof.

21. 2 methyl3-methylamino-7-thiocarbomethylamino-4,5,6,7-tetrahydroindazole or anon-toxic acid addition salt thereof.

22. 2 carbethoxy3-methylamino-7-thiocarbomethylamino-4,5,6,7-tetrahydroindazole or anon-toxic acid addition salt thereof.

23. 2 (4 chloro)-phenyl-3-methylamino-7-thiocarbomethylamino4,S,6,7-tetrahydroindazole or a non-toxic acid addition salt thereof.

24. 2 (4methoxy)-phenyl-3-methylamino-7-thiocarbomethylamino-4,5,6,7-tetrahydroindazoleor a non-toxic acid addition salt thereof.

25. 2 phenyl 3-methylamino-7-carboxy-4,5,6,7-tetrahydroindazole or anon-toxic acid addition salt thereof.

1 N percent:12.38. 2 N D81Cel1t:12.84:.

What we claim is:

1. 2 (4 chloro)-phenyl-3-methylamino-4,5,6,7-tetrahydroindazole or anon-toxic acid addition salt thereof.

2. 2 (4 methoxy)-phenyl-3-methylamino-4,S,6,7-tet- 26. 1(2) benzoyl3-dimethylamino-4,5,6,7-tetrahydroindazole or a non-toxic acid additionsalt thereof.

27. 1(2) (4 chloro) benzoyl-3-dimethylamino- 4,5,-6,7-tetrahydroindazoleor a non-toxic addition salt rahydroindazole or a non-toxic acidaddition salt thereof. thereof.

28. 1(2)-(methoxy) benzoyl 3 dimethylamino- Pocar et a1., Chem. Abst.v01. 59, cols. 2795-6 (1963). 4,5,6,7-tetrahydroindazo1e or a non-toxicacid addition salt thereof. HENRY R. JILES, Primary Examiner ReferencesCted N. TROUSOF, Assistant Examiner Auwers et al., Chem. Abst. v01. 18,pp. 834-6 (1924). 5

Auwers et a1., Chem. Abst. vol 20, p. 389 (1926). S C X-R-Farbenfabriken Bayer Chem. Abst. V01. 60, C01. 6957 260 247 2411 247 2293 293 4 294 32 3 325 (1964)- 326.82, 569, 583, 584; 424 273 Kwartleret al., Jour. Amer. Chem. Soc. vol. 65, p. 1805 relied on (1943). 10

